More than 300 million people around the world have asthma. Despite the use of long-acting bronchodilators and inhaled corticosteroids, asthma continues to be a major source of morbidity worldwide. (Masoli M, et al. Allergy 59: 469-78 (2004)).
Relapse following acute asthma exacerbation has been reported to range from 41 to 52% at 12 weeks despite the use of systemic steroids upon discharge (Lederle F, et al. Arch Int Med 147:2201-03 (1987)). Management of these patients has proved problematic due either to severe refractory disease or inability and/or unwillingness to comply with medical treatment. In one study of patients admitted to the hospital, some with near fatal asthma, 50% were non-compliant with systemic corticosteroids at 7 days following discharge (Krishnan J, et al. AJRCCM 170: 1281-85 (2004)). Many factors may contribute to non-compliance including poor access to routine quality healthcare (particularly in the inner city), lack of education or understanding of their disease, unwillingness to accept the chronic nature of their disease, or inability to obtain medications.
Many lines of evidence implicate eosinophils as one of the main causative cells of asthmatic airway inflammation (James A. Curr Opin Pulm Med 11 (1):1-6 (2005)). Peripheral blood (PB) eosinophilia is a risk factor for relapse of acute asthma (Janson C and Herala M. Resp Med 86 (2):101-104 (1992)). In subjects with peripheral blood eosinophilia, the risk of dying from asthma was 7.4 (confidence interval, 2.8-19.7) times greater than in those without eosinophilia (Ulrik C and Fredericksen J. Chest 108:10-15 (1995)). Necropsy results have identified 2 distinct pathogenic inflammatory mechanisms of fatal asthma (Restrepo R and Peters J. Curr Opin Pulm Med 14: 13-23 (2008)). A neutrophilic infiltrate is more prominent in those dying suddenly (approximately within 2 hours on onset of symptoms), while an eosinophilic infiltrate is more common in those dying from more protracted asthma crises. Sputum and blood eosinophils can also be increased in patients presenting to the ED with rapid onset of asthma symptoms (Bellido-Casado J, et al. Arch Bronconeumol 46 (11): 587-93 (2010)). Therapies that target eosinophils lead to a reduction in the number and severity of asthma exacerbations as compared to the use of clinical guidelines (Green R, et al. Lancet 360:1715-21 (2002); Haldar P, et al. NEJM 360:973-84 (2009)).
Benralizumab (MEDI-563) is a humanized monoclonal antibody (mAb) that binds to the alpha chain of the interleukin-5 receptor alpha (IL-5Rα), which is expressed on eosinophils and basophils. It induces apoptosis of these cells via antibody-dependent cell cytotoxicity. A single intravenous (IV) dose of benralizumab administered to adults with mild asthma provoked prolonged PB eosinopenia likely due to the effects on eosinophil/basophil bone marrow progenitors that express the target (Busse W, et al. JACI 125: 1237-1244 e2 (2010)). In addition, a single dose of benralizumab significantly reduced the blood eosinophil count in subjects who presented to the emergency department with a severe asthma exacerbation, but did not impact Asthma Control Questionnaire (ACQ) scores, which provide an assessment of asthma symptoms (WO 2013/066780).
The ACQ is a patient-reported questionnaire assessing asthma symptoms (night-time waking, symptoms on waking, activity limitation, shortness of breath, wheezing) and daily rescue bronchodilator use and forced expiratory volume in one second (FEV1). Juniper et al., Eur. Respir. J. 14:902-7 (1999) and Juniper et al., Chest 115:1265-70 (1999). Questions are weighted equally and scored from 0 (totally controlled) to 6 (severely uncontrolled). The mean ACQ score is the mean of the responses. Mean scores of ≦0.75 indicate well-controlled asthma; scores between 0.75 and ≦1.5 indicate partly controlled asthma; and a score >1.5 indicates uncontrolled asthma. Juniper et al., Respir. Med. 100:616-21 (2006). Individual changes of at least 0.5 are considered to be clinically meaningful. Juniper et al., Respir. Med. 99:553-8 (2005). The ACQ-6 is a shortened version of the ACQ that assesses asthma symptoms (night-time waking, symptoms on waking, activity limitation, shortness of breath, wheezing, and short-acting β2 agonist use) omitting the FEV1 measurement from the original ACQ score. Other questionnaires, such as the Asthma Therapy Assessment Questionnaire (ATAQ), the Asthma Control Test (ACT), the Asthma Quality of Life Questionnaire (AQLQ), and asthma diaries can also be used to assess asthma symptoms.
Thus, given the high unmet need of improving asthma symptoms, e.g., as measured using the ACQ, and that some patients with asthma have an eosinophilic component, the effect of benralizumab on the asthma questionnaires in adult subjects were examined.